The goal of this project is to focus on one animal model of individual differences in emotional responsiveness to the environment, and to begin to define some of the critical variables that contribute to those behavioral differences. This behavioral model characterizes responsiveness to novelty and other anxiety-provoking situations and distinguishes animals on the basis of whether they are high responders (HR) or low responders (LR). We have already demonstrated that these two groups of rats show significant differences in their stress circuits, in patterns of gene expression in their brain and in their behavioral responsiveness to psychosocial stress. There is ample evidence that the serotonergic system is critical in stress and depression and is the target of an important class of anti-depressants. However, the role of this system in determining individual differences in emotionality remains unknown. In order to further define the neuronal phenotype of these differing animals, this project will use in situ hybridization tools to characterize the expression of serotonergic genes in the hippocampus and cortex of the two groups of animals with different emotional reactivity. It will employ pharmacological tools by locally microinjecting specific 5HT receptor agonists and antagonists in order to link the observed difference in serotonin receptor gene expression to individual differences in anxiety responses. It will also investigate the differential effects of chronic social stress on the neuronal phenotypes of HR and LR animals, and will investigate the actions of multiple classes of anti-depressants on reversing these stress effects. In addition to focusing to focusing on an obvious "candidate' system, this project will use microarray technology to uncover "novel candidates", i.e. other genes that are associated with this behavioral phenotype and are sensitive to chronic social stress. This work will begin to delineate how particular molecules and brain circuits contribute to differences in emotional reactivity.